Scientists discover why Ozempic and Wegovy weight loss eventually plateaus

Researchers at the National Institutes of Health (NIH) have uncovered new details about how GLP-1 weight loss drugs such as semaglutide affect brain cells, revealing internal signaling processes that scientists have only begun to understand. The findings, based on experiments in mice, shed light on why these medications work differently from person to person and why their effects often slow down over time. GLP-1 receptor agonists, including drugs like Ozempic and Wegovy, are already known to hel

Scientists have also identified the brain regions involved in those effects. Until now, however, much less was known about what happens inside the neurons targeted by these drugs. "We know much less about the nuts and bolts of what goes on within the neurons that these medications target. By digging into these mechanisms, we're beginning to answer some of these questions," said co-corresponding author Andrew Lutas, Ph.D., an investigator at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The research team used fluorescence imaging to monitor how semaglutide affected living brain tissue from mice. The work was led by first author Claire Gao, Ph.D., a postdoctoral fellow at NIH's National Institute of General Medical Sciences (NIGMS). By blocking or removing specific signaling molecules inside neurons, the scientists were able to determine which cellular pathways played the biggest role in weight loss effects. Their experiments showed that semaglutide's impact depended heavily on increased levels of cyclic adenosine monophosphate, or cAMP, in the area postrema, a part of the brain involved in appetite regulation. However, the response was not the same in every neuron. "It was not an all or nothing phenomenon. We observed that cAMP responses across cells varied on a continuum," said co-corresponding author Michael Krashes, Ph.D., a senior investigator at NIDDK. Researchers found that some neurons maintained elevated cAMP levels for longer periods while semaglutide was present.

Key points

• Scientists have also identified the brain regions involved in those effects.
• Until now, however, much less was known about what happens inside the neurons targeted by these drugs.
• "We know much less about the nuts and bolts of what goes on within the neurons that these medications target.
• By digging into these mechanisms, we're beginning to answer some of these questions," said co-corresponding author Andrew Lutas, Ph.D., an investigator at NIH's National Institute of Diabetes and D…
• The research team used fluorescence imaging to monitor how semaglutide affected living brain tissue from mice.